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Processes 2015, 3(1), 75-97;

A Computational Study of the Effects of Syk Activity on B Cell Receptor Signaling Dynamics

Department of Mathematics, Purdue University, 150 N. University St., West Lafayette, IN 47907, USA
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 201 S. University Street, West Lafayette, IN 47907, USA
Weldon School of Biomedical Engineering, Purdue University, 206 S. Martin Jischke Drive, West Lafayette, IN 47907, USA
Author to whom correspondence should be addressed.
Academic Editor: Juergen Hahn
Received: 14 October 2014 / Revised: 20 January 2015 / Accepted: 28 January 2015 / Published: 11 February 2015
(This article belongs to the Special Issue Modeling and Analysis of Signal Transduction Networks)
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The kinase Syk is intricately involved in early signaling events in B cells and isrequired for proper response when antigens bind to B cell receptors (BCRs). Experimentsusing an analog-sensitive version of Syk (Syk-AQL) have better elucidated its role, buthave not completely characterized its behavior. We present a computational model for BCRsignaling, using dynamical systems, which incorporates both wild-type Syk and Syk-AQL.Following the use of sensitivity analysis to identify significant reaction parameters, we screenfor parameter vectors that produced graded responses to BCR stimulation as is observedexperimentally. We demonstrate qualitative agreement between the model and dose responsedata for both mutant and wild-type kinases. Analysis of our model suggests that the level of NF-KB activation, which is reduced in Syk-AQL cells relative to wild-type, is more sensitiveto small reductions in kinase activity than Erkp activation, which is essentially unchanged.Since this profile of high Erkp and reduced NF-KB is consistent with anergy, this implies thatanergy is particularly sensitive to small changes in catalytic activity. Also, under a range offorward and reverse ligand binding rates, our model of Erkp and NF-KB activation displaysa dependence on a power law affinity: the ratio of the forward rate to a non-unit power of thereverse rate. This dependence implies that B cells may respond to certain details of bindingand unbinding rates for ligands rather than simple affinity alone. View Full-Text
Keywords: B cell signaling; signal transduction; mutant Syk; computational modeling; cell response B cell signaling; signal transduction; mutant Syk; computational modeling; cell response
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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McGee, R.L.; Krisenko, M.O.; Geahlen, R.L.; Rundell, A.E.; Buzzard, G.T. A Computational Study of the Effects of Syk Activity on B Cell Receptor Signaling Dynamics. Processes 2015, 3, 75-97.

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